Search Results

The 988 Implementation Act was introduced on July 25. What impact will it have on care? On July 25, 2023, Congressman Jamie Raskin and Congressman Tony Cárdenas reintroduced the 988 Implementation Act with Congressmembers Brian Fitzpatrick, Lisa Blunt Rochester, Doris Matsui, Seth Moulton, Grace Napolitano, and Don Beyer. Psychiatric Times sat down with the VP of Government Affairs for Connections Health Solutions, Chris Santarsiero, MBA, to learn more. 988 Implementation Act PT: Can you tell us a bit about the reintroduction of the 988 Implementation Act? Santarsiero: It is an exciting time. A year has gone by since the transition to 988, and there is a lot more work to do to build out the infrastructure, response times, and staffing. For 988 to be truly effective, crisis services must operate in a comprehensive continuum. The 988 Implementation Act provides federal support and funding for states to enact 988 and crisis services, and to broaden awareness of available resources. This will ensure that it’s not just a number to call but a line to connect to services in every community, including trained first responders and crisis centers. Specifically, the 988 Implementation Act: -Solidifies funding for 988 regional and local call centers to ensure a timely 24/7 response to callers anywhere in the country -Provides funding for community-based crisis response, including mobile crisis teams and crisis receiving and stabilization centers -Supports crisis workforce development with increased funding for training and scholarship opportunities -Increases access to care by requiring that all health insurance plans cover crisis services -Implements a national suicide prevention awareness campaign in partnership with a wide array of stakeholders 988 has been a great catalyst to talk about mental health. The mission is a number to call, someone to respond, and a place to go. The 988 Implementation Act really charged that—we are investing in and perfecting it. The launch overall has been very successful, and now we are building out the necessary continuum, which is contingent on what each community’s needs are, what infrastructures are in place, and what needs to be improved upon. What an amazing time to be in the behavioral health arena, because people are finally willing to talk about it openly and acknowledge that more needs to be done. PT: How will this legislation impact patients utilizing Medicare and Medicaid programs? Santarsiero: The Act calls for Medicaid and Medicare coverage. Today, Medicaid is the largest payer of behavioral health services. Even still, there are gaps in care. Our organization is headquartered in Arizona, though we have expanded to and are continuing to expand to other states, and we are fortunate to have structures in place that allow for a continuum like this to take place, but most other parts of the country do not. It also expands upon certified community behavioral health clinics (CCBHCs), the great success of the bipartisan Safer Communities Act. Since the inception of the CCBHC program, in the 10 demonstration states, CCBHCs saw a 60% reduction in emergency room visits; 60% reduction in police visits, jail visits, and police holdings; 33% reduction in homelessness; and 74% reduction in overall hospitalization. It is a wonderful program and a great start. On the Medicaid side, it kind of wraps around the continuum that is needed. On the Medicare side, there is a gap. Medicare does not cover crisis services today. Once Medicare coverage and quality standards are established, then commercial insurance will follow suit—that is typically how it works. The Act also calls for commercial insurers to cover the services as well, which is long overdue. PT: What do you see as the future of 988 and crisis care? Will there be further challenges with sustaining funding? The Renaissance of Behavioral Health: 988 and Crisis Care Santarsiero: I feel great about the future of 988. Recently, a couple more states established sustainable funding through a 988 cell phone surcharge. I think that is a good step. Right now, there is a lot of federal funding for 988 to draw down from, but there are a handful of states that are looking at 988 cell phone surcharges similar to 911. NAMI just came out with some polling data that is very positive: over 80% of those polled approved of a 988 surcharge. There is clearly recognition across the continuum of voters that it is necessary to have parity there. In that regard, I am very optimistic. CMS’ Certified Community Behavioral Health Clinic Demonstration provides a path towards sustainability. Its goal is to improve access to high-quality, integrated behavioral health care for individuals with mental health and substance use disorders. There are 10 states that are already in the CCBHC program, and there are 10 more that will be announced by the middle of next year. That means there will be 20 states with a sustainable funding model directed by Medicaid, but in collaboration with the community-based providers. The Bipartisan Safer Communities Act pretty much ensures that within 8 years, any state that wants to be part of this CCBHC program will be allowed in. It is 10 states every 2 years for the next 8 years. But I also know, in talking with other state leaders and Medicaid agencies and associations, some states are going straight the state plan amendment route, regardless of if they get approved for the next demonstration round. States like Texas and Kansas have already done so. Moves like this leverage the existing structure of Medicaid. I feel good about it in terms of long-term sustainability. PT: Can you talk about the importance of specialized units for individuals experiencing behavioral health emergencies? Santarsiero: It is not easy to talk about folks that are presenting with violent behaviors or suicidal threat to self or others, aggressive behaviors, public intoxication. The system as a whole in most parts of the country has not been equipped to deal with that type of person in crisis. Individuals who are violent, threatening, and in a crisis usually end up in an emergency room or jail. What our model proves is you can have a co-responder model—a partnership with first responders and law enforcement—individuals can get the care they need when they need it most. Our Crisis Response Center (CRC) in Tucson is part of the Tucson Police Department’s Department of Justice Law Enforcement-Mental Health Learning Site Program. Usually, the first people in a community that come to visit are law enforcement, along with county commissioners and sometimes even legislators. To get buy in from first responders first like that… they see there is a better way. At Connections Health Solutions, roughly 50% to 60% of our involuntary patients convert to voluntary status. We get them engaged in their care, and I find that remarkable. Unfortunately, involuntary patients are seen as a population, when the state hospitals are dealing with them, that are just there and constantly in flux. One of the amazing things we are showing with our model is that we can get them engaged and back with their families, which helps solve the homelessness problem. If you are not engaged in your care, families sometimes may no longer want you around. Getting individuals in crisis treated, agreeing to their care, and in a better place—sometimes that is the first step for housing. Then they might agree to a plan of care postcrisis with help from ties to the community. As to maintaining care, some individuals look at readmissions like they are a terrible thing. If they must come back to us, okay—they come back, they get what they need. It is important to talk about this patient population to achieve equity in mental health and establish trust in 988. If we lose those who need us most—those with severe mental illness—we are doing a great disservice. It is important to have that continuum built out in collaboration with all community stakeholders and leaders. Our walk-in centers can treat all acuities up to LOCUS Level 6, but somebody with a LOCUS Level 1, 2, or 3 can still walk in and get behavioral health care. It is important for a community to have a space where they say, “Oh, this is where you can go if you need help,” especially for commercially insured folks who cannot otherwise be seen by a psychiatrist or therapist, and we hope to provide that. PT: What other legislation should mental health clinicians be aware of? Santarsiero: There are a lot of great proposals out there, but the 2 we really focus on are the 988 Implementation Act and the Behavior Health Crisis Services Expansion Act. The latter is going to be reintroduced to Congress by Congresswoman Blunt Rochester from Delaware and Congressman Fitzpatrick from Pennsylvania in the House, and Senator Cortez Masto from Nevada and Senator Cornyn from Texas in the Senate. Clinicians should look at those bills because there are workforce provisions in there, which is great. We are also really excited about is the Biden Administration’s proposed rule on the Mental Health Parity and Addiction Equity Act (MHPAEA). It proposes to significantly improve health plan compliance and strengthen parity enforcement to ensure that people with mental health and substance use disorders do not face arbitrary barriers from insurance providers and receive the care that they need. Connections is currently drafting a written response to address current gaps in access to and provision of a full continuum of behavioral health crisis services. It is 395 pages, but there are 2 pages that have questions and requests for information on crisis. You will have 60 days to comment. It might be good for clinicians to know about this. This is a great opportunity to engage in a rulemaking and to weigh in on a provision. We are excited about the crisis provisions, obviously, but I think overall, it really illustrates the gap in coverage and parity between physical and mental health. Kudos to the administration for doing that. PT: Any final thoughts anything you want to share? Santarsiero: Regarding 988, a few weeks ago I had a conversation with an editor who has been covering Congress since 1995 and he told me, “I think this is the best thing Congress has ever done.” But the irony of that story, is 988 did not happen easily. The legislative process is based on friction, and it took 5 years to pass. I think it's a wonderful catalyst. It is so simple to remember and promote. Now the mission is to ensure a complete continuum for each community in the nation and make it incumbent upon communities to build upon. So many communities are doing such great work now, right down to the state and local level. Communities, stakeholders, law enforcement, first responders, the medical community, the mental health community, and the continuum—as a whole—are working to realize this mission. In 5, 10, or 15 years, we may have an equivalent to 911. I think everybody by and large has confidence in the 911 system. The charge is to be as good, if not better, on the mental health or behavioral health side. There is so much to do, but we are here now, so let's capitalize on it.

My long and complicated lifelong relationship with mental health issues and mainstream psychiatry takes place across three different countries. It all started quite early in my life. I experienced severe emotional neglect and abuse by my parents while growing up. They were respected people; they both had successful careers. They were also both amateur photographers. As a child, I was mainly a prop for their many different projects. And after their divorce, just something to use for expressing their hatred towards each other. During this period, as an unprotected and physically below-average-sized child, I was an easy target for bullying at school, as well as sexual abuse by an older cousin. Then later, around the time of my parents’ divorce, I was sexually abused by the older son of a family friend. Naturally, I developed an eating disorder and OCD at an early age. This wasn’t really taken seriously by the family. I was simply told that I was a spoilt, naughty child who wanted too much attention. I tried really hard to do well at school and be a good enough child for my family, to keep the accusations at bay. Around age 11, I had a classmate commit suicide. He used to sit next to me, and some other children blamed me for his death, because he had left a letter for me. I didn’t know what to make of it, since we weren’t close friends. But after this event, I started visiting the school counsellor frequently. She caused me to blame myself more, but I didn’t see it at the time. The first time I saw a psychiatrist was around age 12. My mother was worried about some sexualised jokes she heard when I was on the phone. Because we didn’t have a close and honest relationship, she just took me to see a professional to put her mind at ease. She was worried I was being promiscuous. The session with the psychiatrist must have worked well for my mother because I only saw this professional once. I assume my mother received positive feedback from the professional and was told not to worry, since I didn’t tell this person anything of importance. Later on, as a teenager, I was subject to more violent and scary sexual abuse, and was forced to use drugs and alcohol by my abuser. I got trapped in a “relationship” and I was unable to escape him. Over time, a severe dissociation took over me. I had to split from my body to cope with what was being done to it. It didn’t feel like my body belonged to me anymore. I started self-harming, just to feel my skin and keep the emotional pain at bay. I was disgusted by my body. At age 15, I was sent to a psychiatrist when I was unable to stay awake for more than a couple of hours, or eat proper food for several days, and my self-harming with sharp objects and cigarettes got too visible and out of control. I tried to open up to the psychiatrist, but he decided that I had a chemical imbalance in my brain and told me the only treatment was medication. I believe he told my parents that I was just seeking attention from them, since my father had recently had a new son from his second marriage and I was expected to react badly to this. An attention-seeking spoilt teenager was the label I had accepted. Despite all the issues, I was still doing very well at school and never getting in trouble with teachers, so this made me look healthy. In reality, I was still being groomed and raped, but now I had the medications to cope with it better. Sadly I had nobody safe in my life who would not react to this information with something like: “How could you be so stupid and allow this to happen to you?” Or “You are lying/exaggerating.” Or “This is all your fault.” So I told no one. The anxiety disorder eventually made me afraid of ever leaving the house alone, or staying at home alone. Thanks to this, the abuser couldn’t have access to me anymore and left me alone. I stayed away from boys after this for over two years. Looking back, I clearly see that my poor body did what it could to protect me under these circumstances, since nobody in my life who had the power to protect me was interested in doing so. I hated the “anxiety disorder” back then, but now I see that it saved my life at the time. I survived to the end of high school. By then my anxiety attacks had morphed into severe agoraphobia, so I was put on antidepressants by the psychiatrist because my agoraphobia was inconvenient for my parents who were busy people. With sufficient antidepressants, my “mental illness symptoms” went away, and so did the negative feelings attached to most of my childhood memories. I didn’t feel my skin or my body much, but I wasn’t aware of this dissociation at that time. The SSRIs also gave me a lot of side effects such as digestive problems, appetite and weight loss, excessive sleepiness, unexplained bruising… But I was told I had to take these long term because apparently the only options I had were either being locked up in a psychiatric unit or taking the medication. At age 17, with enough medication in my system, I wasn’t scared of boys anymore. Thanks to not having the protective emotions I needed (because SSRIs!), I got into a horrific relationship with a drug addict. I stopped worrying about anything, and I stopped going to university. I got pregnant soon after my 18th birthday, and had a secret abortion and paid for it with what I saved from my pocket money. My “boyfriend” contributed to the payment, but he was very shaken by my abortion, so I had to be extra nice to him for a long while. A year or so later, his parents sent him away to another country. I then decided to go to Germany to study at university there, since I had two uncles there who I could stay with. Despite medication, I didn’t feel safe anymore, so I was desperate to leave the country. Germany was good to me until some of my childhood memories started catching up with me again. I tried to quit the SSRIs but the withdrawal symptoms were very severe, so I phoned up the psychiatrist who had put me on them and asked for help. He said it was my original condition coming back and that I wasn’t his patient anymore anyway and not to call him anymore. I searched for a psychotherapist, but could afford none of the ones who had space. The only available therapist that my insurance paid for was a vegan Buddhist. I tried Zen meditation with him for many months but was not getting any better with my anxiety. He was adamant it was because I was not meditating enough. I powered through all this, went to university, worked two jobs, went to the gym, tried to take care of my health. Didn’t help. At age 21, my energy levels were only getting lower and my body weaker. My brain wasn’t functioning the way it used to, which made studying very difficult. I wanted to be safe, and with somebody who would never leave me. I got married. As a result of my issues, my husband was a very controlling and possessive man. I didn’t see how abusive the relationship was, and ignored the violent incidents in his past. I thought if I could control him by behaving however he wanted me to, he would not hurt me. For years, I put all my energy into keeping him happy and his anger under control. He wanted me to give all my attention to him. I quit university again, since he always wanted to do things together and I didn’t have any time and energy left for anything else. I didn’t have any more friends. I rarely saw my relatives who lived in Germany. Eventually, with the referral of a psychiatrist, I voluntarily went into a psychiatric unit, hoping it would be a safe enough place for me to quit the SSRIs and ride out the withdrawal symptoms. Unfortunately they gave me random antipsychotic drugs, which turned me into a panicky mess, since I was not psychotic at all. I managed to get myself out of there, and even the psychiatrist who referred me to the clinic was surprised by their incompetence but he could not offer me therapy and suggested I increase the dose of the SSRIs. I refused and stuck to my usual dose, where I was at least semi-functional. A while later, I found a psychotherapist who did something called Primal Therapy, and had some sessions with him. This was the first time someone was interested in my childhood. This was also the first time I opened up slightly about some of my childhood abuse. However, around this time, due to my husband’s job, we had to move again. This time to England, UK. As a result, I was unable to continue therapy with him. So I went back on full-dose medication and buried the memories one more time. A huge culture shock expected me in England. This time, I didn’t have any relatives or friends. I was all alone. The only person I had was my husband. I tried to distract myself with two part-time jobs. I still wanted to go back to university, but I didn’t have enough money for the fees here. The longer I went without trying to quit SSRIs, the more numb I got, and the less I could remember memories of abuse. The antidepressants also helped me tolerate and normalise mistreatment in my daily life. I wasn’t aware of this at time, of course, but I still didn’t want to use them because the side effects were unbearable. I hardly felt anything, I was like a zombie. I slept too much, found it difficult to communicate with people, and just went along with life. Years went by, the doctors kept prescribing the SSRIs every month, and nobody questioned this very long-term use. I tried to talk to some doctors about quitting, but they discouraged me since I had a ‘chemical imbalance’ in my brain that needed correcting with medication. So I gave up too. Until my late twenties. By then, I was a mother. I knew in my head that I loved my children, but I didn’t feel it in my body. I also realised around this time that I hadn’t cried for years. Realising this level of numbness was too unbearable for me. I could not accept giving my children this kind of mother who did not feel. For over a decade, I had been relying purely on my intellect to live, and had no emotions. Then at age 31, I was lucky enough to come across a kind doctor who genuinely wanted to help me. He suggested that I try quitting my SSRIs extremely slowly, over a period of a year, maybe. He tried to find the medication in small doses or a liquid form to make the tapering easier, but it wasn’t available. So I started tapering by taking half a tablet one day a week, and made a plan to eventually take half two days a week, then three days and so on. After five months I was taking half a tablet every day. And at that point the withdrawal symptoms hit me. All the information I got from the doctor and the internet was that I should not be having these symptoms from simply reducing my dose over such a long period of time. I was on the brink of going back to full dose again when I discovered an American website, a peer support internet forum called “Surviving Antidepressants.” This was a godsend. I had finally found people who could help me quit SSRIs. I adjusted my tapering speed and method according to their recommendations, which was 10% reduction a month, and everything was bearable for a little while. Unfortunately the relief didn’t last long, because the speed of tapering was still too fast for me, due to the fact that I had been on psychotropic medications since age 15, had a huge amount of unprocessed trauma, was stuck in an abusive relationship in a foreign country with no family or friends, as well as having two little children to look after. I sought help from a psychotherapist, who was actually helpful for the first time in my life. I opened up again, purely about the frustrations of SSRI withdrawals, because by this time I had completely forgotten about all my childhood abuse. But I was listened to for the first time, and I was hopeful. However, about a year in, my husband lost his job. We sold our house. We weren’t happy in the new house, and my family were all asking us to move back to my home country. They said that they missed me too much and wanted to have a relationship with my children too. So, we moved back to my home country. In the new country, I wanted to continue therapy with someone local. Because some of my memories were returning due to the reduced dose of SSRIs, or due to being back in the same country and around the same people who abused me. Unfortunately, each psychotherapist or psychiatrist I tried had some method that they were insistent upon using, such as CBT, EMDR, parts work, somatic experiencing… I didn’t feel comfortable with any of those, I just really needed someone to talk to and be understood by. I tried opening up to one of them (a psychiatrist) about early childhood sexual abuse, and she kind of insinuated that sexual experiences are normal in childhood, so I put that idea to bed and decided I was exaggerating it. To be fair to her, a few sessions later, she was the only person who told me that if someone locks you in a room and they have a knife in their hand, and they try to convince the 15-year-old you that they only want to have sex with you because they love you, and when you run away they chase you and in the end you give up fighting and let them do whatever they want, this is still classed as rape. At the time I genuinely thought this experience was all my fault and classed as consensual, since he hadn’t actually stabbed me. Sadly, this psychiatrist also became unavailable, and I eventually gave up on finding someone to talk to face-to-face. Then came 2020 and my living situation became extremely stressful. Family issues were crushing me. I started becoming physically unwell. Then eventually, I developed a very severe chronic illness. Every medical treatment the doctors and hospitals tried on me made me worse. Until my nervous system became so hyper-sensitised that I could not tolerate any medications without dangerous allergic reactions. This slowly spread to different foods, chemicals, materials, temperature changes, even to tap water. I became allergic to life. This stopped me from eating, moving or living as normal people do. At that point I got very depressed and hopeless. My family blamed me as usual, and they assumed that my illness was all in my head. I repeated the mistake of seeking help from psychiatrists, since I was still tapering from a low dose of SSRIs. When I tried to explain my issues, I was told that I had no choice but to go back on a full dose of some kind of psychotropic medication if I ever wanted to get well. The last psychiatrist I saw told me that I was wrong about the side effects of SSRIs and withdrawal symptoms. He did not believe that I never took any other, non-prescribed drugs or used alcohol in over a decade. He said that any other doctors or therapists who ever agreed with me must have been manipulated by me. I had to pay a significant sum of money for the privilege of being insulted and gaslighted, so I will never forget the regret, despair and humiliation I felt after these accusations… Understandably, that was the last time I sought help from mainstream psychiatry. After all these disgusting experiences I had with the mental health system, in three different countries over 20 years, I am not in favour of seeking help from them unless one is at the brink of death. I am now in a place where life seems more hassle than it’s worth. My physical health is in a worse state than my mental health. The medical system broke me completely. The pieces of my shattered soul are waiting to be retrieved from each and every memory of abuse and exploitation. I don’t have the strength to do that alone… So today I am just surviving. I only hold on to life for my children, and nothing else. When I look back at my life, it seems that nobody was interested in actually supporting me. They just wanted me to take the drugs and keep quiet. My family and my rapists, abusers and psychiatrists all had it in common that they wanted me to “take something” to become more obedient and quiet. It is as if they were working together without even knowing each other. The worst part is, I was completely unable to see this pattern until I had a medication-free, clear mind to realise what was being done to me. It is a miracle that we, the victims of psychiatry, ever make it out alive. The system is broken beyond repair… And I hope that the same doesn’t apply to my beaten body and soul. *** Mad in America hosts blogs by a diverse group of writers. These posts are designed to serve as a public forum for a discussion—broadly speaking—of psychiatry and its treatments. The opinions expressed are the writers’ own. *** Mad in America has made some changes to the commenting process. You no longer need to login or create an account on our site to comment. The only information needed is your name, email and comment text. Comments made with an account prior to this change will remain visible on the site.

Service Dog help Veterans When Ryan, 37, returned home from two deployments with the 101st Airborne Division in Iraq from 2005 to 2008, he began withdrawing from social situations and experienced chronic anxiety. Nights brought no respite — his sleep was interrupted by punishing nightmares. "I had every calling card of a veteran in distress," he told Medscape Medical News. When his wife told him she thought he may have posttraumatic stress disorder (PTSD), he shrugged it off. "I wasn't automatically going to accept [the diagnosis] because as an infantry veteran, we're big tough guys. We don't need help with anything." Ryan's wife had heard of a program called Northwest Battle Buddies (NWBB) that pairs professionally trained dogs with veterans struggling with PTSD. The dogs, mostly recruited from rescue organizations, receive 5-7 months of specialized training to assist the veterans. Life-Changing Help While Ryan was skeptical about the program and whether it would work for him, he agreed to try it. After working with Bullet, a cream-colored golden retriever trained to help veterans with PTSD, he realized his life was improving. "I stopped self-medicating, started advocating for myself, and became more comfortable socializing in public." In his 3 years with Bullet, Ryan was able to work on his marriage, advanced his career, and became a homeowner. "The dreams I never thought were attainable started coming to fruition, and I was happy and comfortable for the first time in as long as I could remember." Unfortunately, Bullet died from a rare heart condition after a few years, and when that happened, NWBB immediately began working with Ryan to find him a new dog to fill the void left by Bullet. Soon, Ryan began working with Twitch, who, like Bullet, knew when Ryan was becoming anxious, angry, or depressed before he did, he said. "These dogs pick up on PTSD symptoms and come over and press themselves against you, push their faces into yours, and give you those big puppy dog eyes as if to say, 'I got you. Everything is going to be okay.'" The same thing happened when Ryan had night terrors and nightmares. "These dogs wake you up, and again, you're greeted with this sweet puppy dog face." NWBB founder and CEO Shannon Walker, who has been training dogs for 25 years and whose father served in the US Air Force in the 1950s, leads a 5-week training course for the veterans and their "battle buddies" so that the veterans can learn how to bond with and benefit from their new service dogs. Finding the Perfect Match Veterans are paired with a trained service dog based on their lifestyle and personality. For instance, a Vietnam veteran who is having trouble walking may be paired with a calm dog while a younger veteran who runs each morning is paired with a more active dog. NWBB operates on funds from private donors and nonprofit organizations that make it financially feasible for the veterans to travel to Washington state and stay for the time required to train with their service dogs. "Our service dogs are there in the midnight hour when no one else is," she told Medscape Medical News. "Our veterans are fighting internal battles that no one else sees but the dogs. The dogs alert on their adrenaline and bring them back to the moment of now, interrupting suicidal ideations, panic attacks, and night terrors." Joshua Morganstein, MD, who is chair of the American Psychiatric Association's Committee on the Psychiatric Dimensions of Disaster, told Medscape Medical News that "PTSD can be devastating for service members and veterans and is often associated with comorbid mental health conditions, such as anxiety and substance use." He noted that for many people, dogs and other animals can be an important source of physical, emotional, and psychological comfort. "Programs like the Northwest Battle Buddies are important for us to study and better understand the extent to which trained animals are able to help alleviate the symptoms of PTSD and associated disorders and, perhaps most importantly, enhance the ability of service members and veterans to function and live in ways that feel healthy and productive to them," said Morganstein. He added that the concept of a "battle buddy" is a term pioneered by the US Army in 2002 and describes a "formal, rather than ad hoc, system of peer support in which service members are assigned buddies." "Buddies look out for each other, encourage self-care and self-advocacy and, when needed, help their buddy to seek help. Buddies remind us that someone is looking out for us and there is someone we look out for as well, both of which are protective during difficult times," he said. Source: Medscape

The NCE’s developer has announced that it is now initiating phase 3 studies. A study of a new chemical entity (NCE) for treatment-resistant schizophrenia (TRS) found that 40% of patients improved to the point of no longer meeting TRS severity criteria after 6 months of treatment. Study 014/015—a 6-week, randomized, rater-blinded study by Newron Pharmaceuticals—evaluated the safety, tolerability, and efficacy of evenamide, an investigational NCE for the management of TRS. For study 014, investigators recruited a total of 161 patients with TRS who were consistently administered a therapeutic dose of a single antipsychotic medication, excluding clozapine, with the primary aim of assessing the safety and tolerability of orally administered evenamide at 3 predefined doses: 7.5 mg, 15 mg, and 30 mg twice a day. Preliminary efficacy was evaluated by observing changes in Positive and Negative Syndrome Scale (PANSS) scores from baseline. Secondary objectives involved the evaluation of alterations from baseline in Clinical Global Impression of Change (CGI-C), Severity of Illness (CGI-S), and Strauss-Carpenter Level of Functioning (LOF) scale scores. Study 015 served as an extension of study 014 to investigate the long-term advantages of inhibiting glutamate release, continuing with 77 patients successfully completing 1 year of treatment with evenamide. Results from study 014/015 showed a statistically significant improvement in PANSS, CGI-S, and LOF scores at 6 months (p-value < 0.001: paired t-test, LOCF). A considerable proportion of participants who experienced a > 20% reduction in symptoms compared to baseline on PANSS total score at week 6 had maintained their response upon reevaluation at month 6. No participants experienced a worsening of psychosis, and no participants relapsed. And approximately 40% of participants no longer met the protocol severity criteria used to diagnose treatment resistance upon reevaluation at 6 months. These results were recently presented at the 36th European Clinical Neuropsychopharmacology Congress (ECNP) in Barcelona, Spain. “These highly encouraging results from study 014/015…demonstrate the potential benefits of evenamide and its unique glutamatergic mechanism of action,” said Ravi Anand, Newron chief medical officer, in a press release. “The findings show that the addition of this glutamate modulation to first- and second-generation antipsychotics in patients with TRS potentiates their effects on dopamine dysfunction and can potentially produce a beneficial antipsychotic response. “What is remarkable about the effect of evenamide in this study is that treatment benefits continue to accrue overtime, and many patients who do not respond early achieve clinically important benefits later. Importantly, over the course of the study period, we found that no patients relapsed or experienced worsened psychosis, and a significant portion of patients improved to the point that they no longer met the criteria to enroll in the study to begin with.” Given these results, Newron has announced that it is moving into phase 3 studies of evenamide for the same indication. According to Anand, “Following these encouraging results, which have been assessed by our international advisory committee, we are preparing to initiate a potentially pivotal, phase 3, multinational, randomized, double-blind, placebo-controlled trial in patients with TRS and are confident that the results from that study will endorse the use of evenamide as an adjunct treatment to any other antipsychotic as a new therapeutic strategy for TRS.” Related Topic: Schizophrenia Still Linked to Early Mortality Reference 1. Newron TRS study 6 months’ results: evenamide substantially improves patients to an extent that they no longer meet protocol entry criteria. BusinessWire. October 9, 2023. Accessed October 9, 2023.

Does early improvement in insomnia predict response to pharmacotherapy in psychotic depression? Authors performed a secondary analysis of a randomized clinical trial. CASE VIGNETTE “Mr Penn” is a 34-year-old Caucasian male with a history of recurrent, severe major depressive disorder (MDD) with psychotic features. His most recent psychiatric hospitalization was preceded by a period of significant insomnia with subsequent worsening depression, suicidal ideation with a plan, and an increase in paranoia. During the hospitalization, Mr Penn was started on mirtazapine 15 mg at bedtime. Over the next 7 days, he noted significant improvement in insomnia, with resolution of his suicidal ideation and some improvements in depressive symptoms. At his hospital discharge visit, he asks about whether his dose of mirtazapine should be increased. As his psychiatrist, how would you respond? Insomnia is a common symptom and part of the diagnostic criteria for MDD. A systematic review found that treatment of insomnia improves mood symptoms in MDD. There is some evidence that early insomnia improvement (EII) within the initial weeks of treatment predicts response to antidepressants. However, the clinical utility of EII as a predictor of outcomes of antidepressant treatment remains unclear. There is evidence that psychotic depression (ie, MDD with psychotic features) has a higher severity of insomnia and depressive symptoms and a lower response to antidepressants than nonpsychotic MDD. The Current Study Vos and colleagues6 investigated whether EII predicts response and remission of psychotic depression. The authors performed a secondary analysis of the Dutch University Depression Group (DUDG),7 a double-blind randomized controlled trial of venlafaxine, imipramine, and venlafaxine plus quetiapine in psychotic depression. Participants were aged 18 to 65 years and had a DSM-IV-TR diagnosis of psychotic depression. They had a Hamilton Rating Scale for Depression (HAM-D-17) score of ≥18. Exclusion criteria were no insomnia symptoms at baseline, acute indication for ECT, IA <80, alcohol or substance use disorder in the past 3 months, serious somatic illness, somatic medication affecting mood symptoms, and contraindications for or previous treatment with venlafaxine or imipramine during the current depressive episode. Patients were randomized to 7 weeks of double-blind treatment with venlafaxine, imipramine, or venlafaxine plus quetiapine. A maximum of 3 mg lorazepam per day was also permitted. Depressive symptoms were rated weekly using the HAM-D-17. EII was defined as a ≥20% reduction of insomnia severity (sum of the 3 sleep-related HAM-D-17 items) from baseline after 2 weeks of treatment. Early response for depression was defined as ≥20% reduction in HAM-D-17 score after 2 weeks. The primary outcome measure was response for depression, defined as ≥50% reduction in HAM-D-17 score after 7 weeks (excluding the 3 sleep-related outcomes for the association with EII). Remission of depression was defined as a HAM-D-17 score <8 and the absence of hallucinations and delusions after 7 weeks. Associations between EII and outcomes were analyzed using logistic regression models controlled for age, sex, medication, benzodiazepine use, and pre-treatment insomnia and depression scores. The authors used a last observation carried forward approach for study dropouts. Approximately 114 participants (out of 122 in the original study) met the inclusion/exclusion criteria and were analyzed. Thirty-seven received venlafaxine, 38 imipramine, and 39 venlafaxine plus quetiapine. There were no significant differences in clinical or demographic factors based on the treatment group. The mean participant age was 51 years, and 48% of participants were male. Over the first 2 weeks, the average reduction in insomnia symptoms was significantly greater than other depressive symptoms. EII was achieved in 74% and early response on overall depression in 67% of patients. After 7 weeks, depression response was achieved in 57% and remission in 32%, as well as remission of psychotic symptoms in 67%. EII was a significant predictor of response on overall depression (OR=7.9, 95% CI 2.7-23.4) and depression excluding the 3 insomnia items (OR=6.3m 95% I 2.2-18.3). EII was also a significant predictor of remission of depression (OR=6.1, 95% CI 1.6-23.3) and remission of psychotic symptoms (OR=4.1, 95% CI 1.6-10.9). There were no significant interactions between EII and medications. EII had a higher sensitivity and negative predictive value than early depression response for all outcome measures. Study Conclusions The authors performed the first study of EII as a predictor of treatment outcome in psychotic depression. They found evidence that EII was associated with depression response and remission and remission of psychosis. Insomnia symptoms improved within the first weeks of pharmacotherapy, whereas depressive symptoms improved more gradually. Study strengths include a more homogeneous sample of patients with psychotic depression, and the fact that patients were free of other psychotropics (except possibly low-dose benzodiazepines). Limitations include the lack of data on pre-study benzodiazepines and the lack of a specific insomnia scale. The Bottom Line Early improvement in insomnia was associated with a higher response to depressive and psychotic symptoms in psychotic depression. Further studies are needed to investigate the generalizability of EII as a predictor of treatment response in depression. Dr Miller is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric Times®. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute. Related topic: What are Sleep/Wake Disorders? References 1. Gebara MA, Siripong N, DiNapoli EA, et al. Effect of insomnia treatments on depression: a systematic review and meta-analysis. Depress Anxiety. 2018;35(8):717-731. 2. Cao B, Park C, Rosenblat JD, et al. Changes in sleep predict changes in depressive symptoms in depressed subjects receiving vortioxetine: an open-label clinical trial. J Psychopharmacol. 2019;33(11):1388-1394. 3. Wang M, Zhang B, Zhou Y, et al. Sleep improvement is associated with the antidepressant efficacy of repeated-dose ketamine and serum BDNF levels: a post-hoc analysis. Pharmacol Rep. 2021;73(2):594-603. 4. Manber R, Buysse DJ, Edinger J, et al. Efficacy of cognitive-behavioral therapy for insomnia combined with antidepressant pharmacotherapy in patients with comorbid depression and insomnia: a randomized controlled trial. J Clin Psychiatry. 2016;77(10):e1316-e1323. 5. Jääskeläinen E, Juola T, Korpela H, et al. Epidemiology of psychotic depression - systematic review and meta-analysis. Psychol Med. 2018;48(6):905-918. 6. Vos CF, Birkenhäger TK, Nolen WA, et al. The relationship of early sleep improvement with response to pharmacotherapy in unipolar psychotic depression [published online ahead of print, 2023 Aug 31]. J Clin Psychopharmacol. 2023;10.1097/JCP.0000000000001756. 7. Wijkstra J, Burger H, van den Broek WW, et al. Treatment of unipolar psychotic depression: a randomized, double-blind study comparing imipramine, venlafaxine, and venlafaxine plus quetiapine. Acta Psychiatr Scand. 2010;121(3):190-200.

Over the past 2 decades, the attention-deficit/hyperactivity disorder (ADHD) treatment spectrum has expanded to include intermediate-acting and long-acting treatments. Despite the advances in drug delivery technology for stimulant medications, short-acting stimulants remain widely prescribed for adults with ADHD.1,2 Understanding the diverse mechanisms and pharmacokinetic profiles of the currently available group of long-acting stimulant formulations will help clinicians tailor treatment to individual patient needs. In a recent Psychiatric Times® Expert Perspectives video series, Greg Mattingly, MD, associate clinical professor at Washington University School of Medicine in St Louis, Missouri, and president-elect of the American Professional Society of ADHD and Related Disorders (APSARD); and Oren Mason, MD, family physician at Attention MD in Grand Rapids, Michigan; had a wide-ranging discussion highlighting key points from a presentation they delivered at the 2023 APSARD annual meeting. They examined how the landscape of stimulant medications has evolved and how to improve the patient experience with stimulants. Ahead is a summary of key points and clinical insights from the discussion. Evolving Treatment Landscape for Adult Patients With ADHD As explained by Dr Mattingly, many long- acting medications achieve their duration of action by combining various ratios of immediate-release and extended-release components, which results in 2 peaks on the pharmacokinetic (PK) curve. “That first pulse [corresponds] to an immediate-release component, and the later pulses [are] delayed-release components that [occur] throughout the day… Formulations with immediate-release components usually have what we call a biphasic pharmacokinetic profile,” said Dr Mattingly. “[This means] that patients may potentially feel the on/off periods or the [adverse] effects of medicines [in a] coming-and-going [manner] rather than feeling the full duration of coverage.” Guidance for Prescribing Stimulants in Adults Within the past 15 to 20 years, the diagnosis of ADHD has increased to a greater extent for adults than for children and adolescents. In fact, a 2021 global systematic review and meta-analysis found a global prevalence of 8.83% in adults around the world. When treating adult patients with ADHD, Dr Mattingly noted that understanding various PK profiles can optimize treatment decision-making for patients with ADHD who may have disparate needs. He explained that for agents that contain a higher proportion of immediate-release medication, patients tend to exhibit greater early medication exposure relative to total exposure. “Typically, [this] is reflected by an earlier onset of action,” he said, “but perhaps [it does not have] sustained duration of action.” In comparison, Dr Mattingly said, “Formulations that have less drug available in immediate release but have more of the [medication acting in] extended release tend to give [the patient] a longer duration of coverage.” Dr Mattingly went on to describe multiple technologies that have different PK profiles. “They all need to be understood to optimize the outcomes for your patients,” he said. According to Dr Mattingly, advantages of long-acting formulations include: improving or augmenting symptom coverage throughout the day, potentially improving treatment response, helping with adherence, and potentially improving tolerability without having the on/off effect. He also added, “It’s breaking the barriers of stigma and improving privacy.” He concluded that currently, guidance is to shift away from short-acting agents whenever appropriate. Clinician and Patient Perspectives on Stimulants for ADHD Keeping the benefits of long-acting stimulants in mind, clinicians can improve the patient experience when treating adult ADHD. According to Dr Mason, the goal of treatment is to improve symptoms and to achieve functional remission, which is when the functional impairments begin to normalize. “In my experience, [although] people understand a small bit about ADHD, [patients] may not understand the full impact of ADHD on their lives,” said Dr Mason. “When we prescribe these medications, we should literally see the changes across [their full] spectrum of symptoms.” When treating adult patients with ADHD, Dr Mason explained that despite the benefits of long-acting stimulants, many patients ask for short-acting stimulant medications. “[They may have] concerns about cost or fear of the medications, hoping to limit their exposure to something they don’t understand,” said Dr Mason. “I think we have to explore it with people. There’s a lot of reassurance we can give. [We can explain] that these medications don’t change personality when properly administered, patients have overwhelmingly positive experiences to them, and a trial of [long-acting] medication may help educate them about the [benefits] that they might see from ADHD medication therapy.” In addition, it’s important for clinicians to consider medication duration. Dr Mason said that clinicians can give patients an expectation of what the average patient might experience; they will, however, need additional education to understand when a medication is wearing off. To achieve adequate duration, clinicians should begin with prescribing long-acting medications to achieve an all-day duration, according to Dr Mason. “An all-day duration is simply not going to [be achieved] with a short-acting medication, a medication [with effects that only last] for 4 to 6 hours,” said Dr Mason. “We let patients know what we expect the duration of benefit to be, and then we actually measure it. If the duration is inadequate, [we’ll] either switch to another long-acting preparation or, in some cases, we’ll add a short-acting booster to lengthen the duration of benefit.” He went on to explain that with many longer-acting preparations, there is an improvement in duration of benefit, not just in midday effect. “Through the titration optimization, we need to ask questions about both efficacy and duration of benefit. If we’re not able to obtain adequate duration of benefit from one long-acting medication, we have others that we can try. If no long-acting preparation gives the patient the duration necessary, we can add short-acting boosters in the afternoon.” Keeping in mind the appropriate utilization of stimulants and the avoidance of the overuse of short-acting formulations, Dr Mason highlighted current stimulant prescribing practices and clinician perspectives about treating adults with ADHD, explaining that there is a trend of improvement across the medical spectrum, despite the need for more improvement in the landscape.“ ADHD management spans a range of specialties, and [there are] different practices within each. We looked at a 2017 cross-sectional study across US-based health care professionals. For the purpose of the study, we’re going to talk about 4 specialties: psychiatrists, neurologists, primary care doctors, and psychiatric nurse care practitioners. When asked to identify which pharmacotherapy they prescribe as first-line treatment, short-acting stimulants were cited by 17% of psychiatrists and 29% to 36% of the other 3 groups. This means that there [are] a lot of short-acting stimulants being used primarily for ADHD right out of the gate. Psychiatrists are more likely than the other groups to prescribe long-acting stimulants.” In addition, health care professionals were asked how strongly they agree or disagree with the following statement: It’s difficult to determine optimal ADHD treatment regimen for adult patients. According to Dr Mason, there was a resounding yes from 45% of psychiatrists and 60% of primary care physicians, neurologists, and nurse practitioners. “This is an opportunity for education,” he said. “We need more awareness about the actual benefits of the [long-acting] medications, the deficiencies of short-acting medications relative to long-acting stimulants, and the opportunity to do better for our patients.” Despite the benefit patients can yield from ADHD medications, there are unmet needs that remain. According to Dr Mason, adequate duration of effect is an area in need of improvement, especially for adults with ADHD. “Clinicians should be aware of how the method of extending duration [with short-acting agents] influences drug pharmacokinetics,” he said. “Health care professionals have identified a need for guidance regarding stimulant medications for ADHD.” Dr Mattingly added that patients who misperceive the energizing effects of stimulants for clinical benefit may drive a preference for short-acting stimulants. As the role of long-acting medications within the spectrum of ADHD treatment continues to evolve, Dr Mason said that there is a need for more education related to the benefits of long-acting medications relative to short-acting stimulants to help improve patient outcomes. References 1. Cascade E, Kalali AH, Weisler RH. Short-acting versus long-acting medications for the treatment of ADHD. Psychiatry (Edgmont). 2008;5(8):24-27. 2. Mattingly GW, Wilson J, Ugarte L, Glaser P. Individualization of attention-deficit/hyperactivity disorder treatment: pharmacotherapy considerations by age and co-occurring conditions. CNS Spectr. 2021;26(3):202-221. doi:10.1017/S1092852919001822 Related Topic: ADHD Underappreciated in Older Adults

Antidepressant ARCELONA — The typical lag between treatment initiation with selective serotonin reuptake inhibitors (SSRIs) for depression and enhanced mood may be because of the time it takes to increase brain synaptic density, new imaging data suggest. In a double-blind study, more than 30 volunteers were randomly assigned to the SSRI escitalopram or placebo for 3-5 weeks. Using PET imaging, the investigators found that over time, synaptic density significantly increased significantly in the neocortex and hippocampus but only in patients taking the active drug. The results point to two conclusions said study investigator Gitta Moos Knudsen, MD, PhD, clinical professor and chief physician at the Department of Clinical Medicine, Neurology, Psychiatry and Sensory Sciences, at Copenhagen University Hospital, Copenhagen, Denmark. First, they indicate that SSRIs increase synaptic density in brain areas critically involved in depression, a finding that would go some way to indicating that the synaptic density in the brain may be involved in how antidepressants function, "which would give us a target for developing novel drugs against depression," said Knudsen. "Secondly, our data suggest synapses build up over a period of weeks, which would explain why the effects of these drugs take time to kick-in," she added. The findings were presented here at the 36th European College of Neuropsychopharmacology (ECNP) Congress, and simultaneously published online in Molecular Psychiatry. Marked Increase in Synaptic Density SSRIs are widely used for depression as well as anxiety and obsessive-compulsive disorder. It is thought they act via neuroplasticity and synaptic remodeling to improve cognition and emotion processing. However, the investigators note clinical evidence is lacking. For the study the researchers randomly assigned healthy individuals to either 20-mg escitalopram or placebo for 3-5 weeks. They performed PET with the 11C-UCB-J tracer, which allows imaging of the synaptic vesicle glycoprotein 2A (SV2A) in the brain, synaptic density, as well as changes in density over time, in the hippocampus and neocortex. Between May 2020 and October 2021, 17 individuals were assigned to escitalopram and 15 to placebo. There were no significant differences between two groups in terms of age, sex, and PET-related variables. Serum escitalopram measurements confirmed that all participants in the active drug group were compliant. When synaptic density was assessed at a single time point, an average of 29 days after the intervention, there were no significant differences between the escitalopram and placebo groups in either the neocortex (P = .41) or in the hippocampus (P = .26). However, when they performed a secondary analysis of the time-dependent effect on SV2A levels, they found a marked difference between the two study groups. Compared with the placebo group, participants taking escitalopram had a marked increase in synaptic density in both the neocortex (rp value, 0.58; P = .003) and the hippocampus (rp value, 0.41; P = .048). In contrast, there were no significant changes in synaptic density in either the neocortex (rp value, -0.01; P = .95) or the hippocampus (rp value, -0.06; P = .62) in the hippocampus. "That is consistent with our clinical observation that it takes time to evolve synaptic density, along with clinical improvement. Does that mean that the increase in synaptic density is a precondition for improvement in symptoms? We don't know," said Knudsen. Exciting but Not Conclusive Session co-chair Oliver Howes, MD, PhD, professor of Molecular Psychiatry, King's College London, London, United Kingdom, agreed that the results do not prove the gradual increase in synaptic density the treatment response lag with SSRIs. "We definitely don't yet have all the data to know one way or the other," he told Medscape Medical News. Another potential hypothesis, he said, is that SSRIs are causing shifts in underlying brain circuits that lead to cognitive changes before there is a discernable improvement in mood. Indeed, Howes suggested increases in synaptic density and cognitive changes related to SSRI use are not necessarily dependent on each other and could even be unrelated. Also commenting on the research, David Nutt, MD, PhD, Edmond J. Safra Professor of Neuropsychopharmacology at Imperial College London, United Kingdom, said that the "delay in therapeutic action of antidepressants has been a puzzle to psychiatrists ever since they were first discerned over 50 years ago." "So, these new data in humans, that use cutting edge brain imaging to demonstrate an increase in brain connections developing over the period that the depression lifts, are very exciting." Nutt added the results provide further evidence that "enhancing serotonin function in the brain can have enduring health benefits." Funding support was provided by the Danish Council for Independent Research, the Lundbeck Foundation, Rigshospitalet, and the Swedish Research Council. Open access funding provided by Royal Library, Copenhagen University Library. Knudsen declares relationships with Sage Biogen, H. Lundbeck, Onsero, Pangea, Gilgamesh, Abbvie, and PureTechHealth. Another author declares relationships with Cambridge Cognition, and PopReach via Cambridge Enterprise. 36th European College of Neuropsychopharmacology (ECNP) Congress. Abstract S14.04 and P.0378. Presented October 8 and 9, 2023.

Disruptions TOPLINE: US adults with psychiatric illness experienced fewer disruptions in receiving psychotherapy following the transition to virtual psychiatric care that accompanied the onset of the COVID-19 pandemic, a large study has shown. METHODOLOGY: Retrospective study using electronic health records and insurance claims data from three large US health systems. Sample included 110,089 patients with mental health conditions who attended at least two psychotherapy visits during the 9 months before and 9 months after the onset of COVID-19, defined in this study as March 14, 2020. Outcome was disruption in psychotherapy, defined as a gap of more than 45 days between visits. TAKEAWAY: Before the pandemic, 96.9% of psychotherapy visits were in person and 35.4% were followed by a gap of more than 45 days. After the onset of the pandemic, more than half of visits (51.8%) were virtual, and only 17.9% were followed by a gap of more than 45 days. Prior to the pandemic, the median time between visits was 27 days and after the pandemic it dropped to 14 days, suggesting individuals were more likely to return for additional psychotherapy after the widespread shift to virtual care. Over the entire study period, individuals with depressive, anxiety, or bipolar disorders were more likely to maintain consistent psychotherapy visits, whereas those with schizophrenia, ADHD, autism, conduct or disruptive disorders, dementia, or personality disorders were more likely to have a disruption in their visits. IN PRACTICE: "These findings support continued use of virtual psychotherapy as an option for care when appropriate infrastructure is in place. In addition, these findings support the continuation of policies that provide access to and coverage for virtual psychotherapy," the authors write. SOURCE: The study, led by Brian K. Ahmedani, PhD, with the Center for Health Policy and Health Services Research, Henry Ford Health, Detroit, Michigan, was published online October 11 in Psychiatric Services. LIMITATIONS: The study was conducted in three large health systems with virtual care infrastructure already in place. Researchers did not examine use of virtual care for medication management or for types of care other than psychotherapy, which may present different challenges. DISCLOSURES: The study was supported by the National Institute of Mental Health. The authors have no relevant disclosures. Related topic: Telehealth What Happens When There Is No Help?

GLP-1 Agonists and Suicide Risk A statement from the European Medicines Agency (EMA) about semaglutide and, more generally, glucagon-like peptide 1 (GLP-1) agonists recently caused a stir. Could these medicines lead to patients taking their own lives? Medical Authorities Alert The EMA published a press release in early July 2023 to announce that a review is underway after reports from the Icelandic Medicines Agency about two cases of patients who developed suicidal thoughts while taking liraglutide (Saxenda) and semaglutide (Ozempic). There was also a report of self-injury in a patient taking liraglutide. Clearly, a few cases aren't enough to call an entire therapeutic class into question or to establish contraindications. Further investigation is needed, and the European authorities who collected the data are analyzing the approximately 150 reports concerning possible cases of self-injury and suicidal thoughts in patients taking these drugs. We should have some results and answers by November 2023. This alert comes at a time when GLP-1 agonists, especially semaglutide, are being misused, particularly in France. The French health authorities (ANSM) have published a press release and reiterated that these medicinal products should be used only as indicated. Despite these warnings, alerts, and suspicions, the risk profile of GLP-1 agonists appears to clinicians to be very good. Although nausea and vomiting occasionally lead patients to stop treatment, there are no obvious major side effects. A risk for acute pancreatitis (though not yet fully confirmed) has been mentioned, as has a risk for thyroid cancer that has not fully been proven in humans. Do we now have to worry about suicide risk? Another Rimonabant Fiasco? This situation is reminiscent of what happened with rimonabant (Acomplia), which was studied and marketed in the early 2000s. Relatively soon after it reached the market, it was withdrawn, mainly because of a risk for depression and suicide. Is this a case of history repeating itself? Have we found ourselves in the same situation? Frankly, as it stands, I don't think so. It's true that with rimonabant, we had some worrying data that had already been observed in randomized clinical trials. There were already signs of mood disturbances in patients taking the drug vs placebo. With GLP-1 agonists, to my knowledge, there have been no reports of this kind in the clinical trials conducted. Of course, this doesn't rule out a rare risk. That's why we need to continue with the investigations. We also know that there are GLP-1 receptors in the central nervous system. We often talk about them as being located in the hypothalamus, which largely explains the effect of these drugs on appetite. But the mechanisms of action of GLP-1 agonists and medicines conventionally used to reduce appetite (anorectics or even rimonabant) are very different. This is why we don't really expect there to be any psychological side effects with GLP-1 agonists. What's the Explanation? Why do we have these suspicious observations of suicidal ideation or self-injury? What are the possible explanations? In my opinion, we must first confirm that the incidence of these psychiatric disturbances is greater in patients taking GLP-1 agonists than in a similar matched general population group. We should also question whether these mood disturbances are not simply linked to patients with obesity who have easy access to GLP-1 agonists. We know that obesity is associated with an increased risk for suicidal ideation and self-injury. There is another little-known observation: Weight loss is associated with a risk for suicide. It has been spoken about in relation to bariatric surgery. We know that after bariatric surgery (bypass or sleeve gastrectomy) the risk for suicidal ideation is double that of the preoperative period in the same population. And this risk is multiplied by close to four when comparing the population with a control group. But be careful because these data come from observational studies. Although the analysis I'm referring to when I'm speaking in relation to a control population is a control group, it isn't from a randomized trial. There is another interesting piece of data, which is that weight loss, regardless of the method used, is associated with an increased risk for suicide. This is what I found in two prospective studies involving this association, and there is no obvious explanation for it at this stage. Of course, there are lots of types of methodologic bias possible, but this poses the question of why there is a greater risk for suicide and self-injury in people taking a certain treatment and losing weight. In Practice Should we change our attitude towards prescribing GLP-1 agonists? For the moment, there are no recommendations in this regard. I don't think that it's reasonable to upend everything. Of course, the important thing is to adhere strictly to the treatment indications, and in a few weeks' time, we'll see the results from the analyses conducted by the French Health Authorities regarding the causal link between suicide risk and taking a GLP-1 agonist. With our current knowledge, I think we can all agree that losing weight is never a walk in the park. It's a change, for which individual physical and psychological consequences must be measured. Related Topic: Study Supports Efficacy of 9-Item Depression Screening in Identifying Patients at Risk for Suicide

Esketamine Bests Quetiapine for Severe Depression in Head-to-Head Trial BARCELONA — Intranasal esketamine (Spravato, Janssen) is superior to extended-release quetiapine (Seroquel, AstraZeneca), an atypical antipsychotic, for treatment-resistant depression (TRD), results of a large, multicenter, head-to-head phase 3 trial show. Results from the ESCAPE-TRD study, which included 675 participants with TRD, show that esketamine was associated with significantly increased rates of both depression and functional remission in comparison with quetiapine. More than 675 patients were randomly assigned to receive one of the two drugs along with ongoing treatment with a selective serotonin reuptake inhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor (SNRI). Esketamine increased remission rates at 2 and 8 months over quetiapine by 72% and raised functional remission rates at 8 months by 88% while decreasing adverse event rates. The findings were presented here at the 36th European College of Neuropsychopharmacology (ECNP) Congress and were published online October 5 in The New England Journal of Medicine. New Hope The results provide "some hope for our patients suffering from TRD, which, given the data, is somewhat of a misnomer," said study investigator Andreas Reif, MD, professor of psychiatry, psychosomatic medicine, and psychotherapy, University Hospital Frankfurt–Goethe University, Frankfurt am Main, Germany, and president-elect of the ECNP. "These patients are not resistant, they just have resistance to monoaminergic drugs," he added. Esketamine, he said, is a "new weapon in our armamentarium." Reif said TRD is a serious condition that affects approximately 20% to 30% of those with major depressive disorder and has "substantial impact" on patients' lives, including quality of life and level of functioning. "We know that esketamine nasal spray is effective in TRD. However, up to now, there were only placebo-controlled trials in addition to ongoing antidepressant treatment," Reif noted. Consequently, he added, a head-to-head comparison with an active agent with proven efficacy was "urgently needed." For the trial, patients from 171 sites in 24 countries with TRD, defined as a <25% improvement in symptoms with two or more consecutive treatments of adequate dosage and duration, were randomly assigned to receive esketamine nasal spray (n = 336) or quetiapine (n = 340) extended release together with ongoing SSRI or SNRI therapy. Both esketamine and quetiapine were flexibly dosed. The primary endpoint was rates of remission at week 8 on the Montgomery–Åsberg Depression Rating Scale (MADRS). After week 8, patients entered a maintenance phase that lasted to week 32. Reif said the study population was representative of a typical TRD population. The average duration of the current depression episode was more than 5 years, and the average MADRS score was above 30. Key Findings Results showed that those who received esketamine in combination with an SSRI or SNRI experienced a significantly higher rate of remission at week 8 compared to those treated with quetiapine (27.1% vs 17.6%; P = .003). This equated to an adjusted odds ratio (OR) for remission of 1.74 (P = .003). Use of esketamine was also associated with a higher rate of remission at week 8, and patients remained relapse free at week 32 (21.7% versus 14.1% with quetiapine; OR, 1.72 (P = .008). At every time point through the study, the proportion of patients experiencing remission was significantly greater with esketamine than with quetiapine. The absolute rate of remission at week 32 was 55.0%, vs 37.0% (P < .001). Reif noted that the definition of remission used in the study was a MADRS score of ≤10, but if the "more lenient" definition of ≤12, which has been used previously, were to be applied, the absolute remission rates would rise to 65.1%, vs 46.7%. Reif also presented results on functional remission rates beyond 32 weeks ― data that were not included in the study as published in NEJM. While remission rates increased over time in both study arms, the functional remission rate at week 32 was, again, significantly higher with esketamine than with quetiapine (38.1% vs 25.0%; OR, 1.88; P < .001). The safety data revealed no new signals, Reif said. Use of esketamine was associated with a lower rate of treatment-emergent adverse events that led to treatment discontinuation, at 4.2% vs 11.0% with quetiapine. Among patients given the ketamine-derived drug, there were lower rates of nervous system disorders, and there were no incidences of weight gain, fatigue, or hangover. Reif said the results show that esketamine nasal spray was superior to quetiapine in achieving remission over time and that it "greatly improves patients' functional impairment" while achieving "generally lower" adverse event rates. He added that they are currently running a significant number of secondary analyses "to give us a better grasp of which patient benefits most" from esketamine therapy over quetiapine. The results may potentially be used to guide patient selection. "Tremendous Advance" Session co-chair Mark Weiser, MD, chairman at the Department of Psychiatry, Sackler School of Medicine, Tel Aviv University, Israel, told Medscape Medical News the results are "very exciting" and offer "further proof of a tremendous advance in our field." Weiser, who was not involved in the study, added that demonstrating functional improvement with esketamine was key. "It's great to improve symptoms," he said, "but to have patients show an improvement in their functionality is really the bottom line of this. Not only do you feel better, but you function better, and that's of extreme importance and makes us feel very optimistic about the future." Also commenting, Josep Antoni Ramos-Quiroga, MD, PhD, head of psychiatry, Vall Hebron University Hospital and Autonomous University of Barcelona, Barcelona, Spain, welcomed the findings. "The results of this study show the superior response and safety of esketamine nasal spray when compared with quetiapine," he said in a release. "This gives people with treatment-resistant depression more safe treatment options." The study was funded by Janssen EMEA. Reif has relationships with Boehringer Ingelheim, COMPASS, Janssen Pharmaceuticals, LivaNova USA, Medice, Saga Therapeutics, and Shire. Other authors have disclosed numerous relationships with industry. 36th European College of Neuropsychopharmacology (ECNP) Congress: Abstract S06.04. Presented October 8, 2023.

Editor's note: Find the latest long COVID news and guidance in Medscape's Long COVID Resource Center. As many as 2 out of 3 people with long COVID also have mental health challenges, including high rates of depression and anxiety, new research shows. It's a surprising finding that shows that those with long COVID may experience more mental distress than people with other chronic illnesses, such as Alzheimer's disease, cancer, diabetes, and cardiovascular disease. The study, published in The Lancet, followed 236,379 patients with long COVID. The investigators found that 62% of patients had received either a neurologic or a psychological diagnosis 6 months after being diagnosed with acute COVID. Mental distress associated with long COVID is a complex phenomenon that has biological, psychological, and social components, said Anna Dickerman, MD, a psychiatrist with New York–Presbyterian Hospital/Weill Cornell Medicine and associate professor of clinical psychiatry at Weill Cornell Medical College. This means that biological underpinnings caused by long COVID affect brain chemistry and give rise to psychological changes, putting a patient at higher risk for depression and anxiety, she said. In turn, changes in mental health can affect a person's risk of social effects such as job loss, disability, and isolation, which can affect self-esteem and self-worth, compounding anxiety and depression. Among patients with long COVID, all of these factors come together to cause what Dickerman has called "a perfect storm" that often results in depression, anxiety, and in some cases, suicidal thoughts. Dickerman and her colleagues at New York–Presbyterian Hospital are working to understand the mental health effects of long COVID so that patients are better able to recover from both the physical and mental health effects of this chronic condition. In an interview, Dickerman explained the mental health implications for people with long COVID and for the doctors who treat them. Excerpts of the interview follow. How does long COVID cause changes in the brain that result in depression? Long COVID causes inflammation in the brain that can cause the release of cytokines (proteins that are secreted from certain cells in the immune system) that are known to cause...fatigue, low energy, and low motivation ― symptoms which are also associated with depression and anxiety. What's more, if a patient had a serious case of acute COVID which led them to go on a ventilator, that too can cause changes in the brain. This means they could have had problems with their oxygenation status, and oxygen deprivation can have both acute and long-term effects on the brain. People can become delirious, meaning they have disturbances in their cognitive function, like attention and awareness (deficits). Patients may also have received steroids for treatment, which have been shown to impact mood and cause depression and anxiety. It's difficult to parse out because problems with attention and memory can also be associated with depression. Teasing apart what's from depression and what's from long COVID is tricky, but we do know that there's something unique about long COVID that causes cognitive deficiencies and changes. How do other factors associated with long COVID, such as insomnia, pain, and fatigue, affect the onset of depression and anxiety? Insomnia itself can be a symptom of depression. It may also be a physical symptom of long COVID similar to pain or difficulty breathing. And if you're not sleeping well, you're going to feel worse both physically and mentally. We also know that pain can affect mood and mood can affect pain — it's a bio-directional relationship. For example, if you're in pain, you're going to feel bad, and if you're depressed, that can also make your pain experience worse. Additionally, if you're in pain, it causes a physical limitation that can keep you from work or seeing your friends and family. These can all impact your social life. Limitations at work can also cause financial stress, which has been shown to impact mental health. Basically, it's a snowball effect that can make you more depressed, and the more depressed you become, the less you're able to participate in the activities that bring you happiness. Are rates of suicide higher in those with long COVID? Multiple studies have shown increased rates of suicidal ideation (thoughts) in patients with long COVID — and it's likely correlated with the degree of physical symptom burden, especially pain. This is consistent with what the research shows us of other chronic illnesses. In terms of specifically quantifying rates of completed suicides in the long COVID population, we simply need more epidemiological data. For now, I would say it's important for providers and the general population to know that these patients may be at increased suicide risk and to screen accordingly. Who is most at risk for mental distress associated with long COVID? Certainly anyone who had a preexisting mental health history before they got long COVID would be at a higher risk. There also seems to be disproportionate effects in those who have stressors related to other social determinants of health, like discrimination, poverty, and healthcare access. As a result, Black and Hispanic minority groups would be at a disproportionate risk for bad outcomes related to long COVID. What are the most effective treatments for those who have mental health problems associated with long COVID? This work is ongoing, and in the coming years we're likely to see new interventions. But for now, what we have in our treatment arsenal is the same evidenced-based treatments for anxiety and depression that we have in patients who don't have long COVID. For example, if a patient meets the clinical criteria for a major depressive episode or an anxiety disorder and they have long COVID, treatment would involve things like antidepressants and cognitive-behavioral therapy. Experts may also recommend a grated, gradual increase in physical activity in some patients with long COVID–associated depression. As a result of the number of people who got COVID, is there now an epidemic of mental health problems associated with the condition? In general, we're in the midst of a mental health epidemic as a result of the pandemic and all the effects that it's had on society, whether or not people had COVID. We're definitely seeing higher rates of depression and anxiety than we did before the pandemic. It's a group of patients that need attention. We also need more research over the next few years so that we can figure out better targeted treatments for this patient population. But for now, we know that it's important to work in an interdisciplinary model where we have psychiatrists working in close collaboration with pulmonologists, general practitioners, and cardiologists to holistically address both the physical and mental issues and not treat them in isolation, because we know there's a relationship.

The risk for depression following retirement is higher in individuals who retire later in life, according to study findings published in The American Journal of Geriatric Psychiatry. Women and individuals living in rural areas seem particularly impacted. Thus far, most studies exploring retirement age and depression have been primarily conducted in Northern European countries with social welfare systems that provide significant support for pensions and employment, contributing to better mental health after retirement. Taiwan (with low labor force participation rates, long working hours, stressful working conditions, and the fastest current rate of population aging globally) is trending toward delayed statutory retirement age and prolonged working life, and the impact this environment may have on later-in-life depression has not been thoroughly explored. Therefore, investigators in Taiwan aimed to determine if retirement is associated with depressive disorders and if retirement age is a mitigating factor. The investigators conducted a population-based study using Taiwan’s National Health Insurance (NHI) dataset from January 2000 to December 2019. The NHI program in Taiwan enrolls about 99% of the national population and the dataset includes 2 million citizens determined by randomized sampling. The investigators identified 84,224 individuals who were aged 50 years and older, employed at the baseline, and had records of retirement during the follow-up period. The International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) codes were used to track the incidence of depressive disorders in the 7 years before and after retirement. "Instead of implying a beneficial mental effect of retirement, our results highlight that retirement represents a major life change and a potential stressor for older adults." The investigators found that age of retirement was oldest among those who had depression incidence before retirement (n=5111; 6.1%) and youngest among those with depression incidence after retirement (n=5222; 6.2%). For the subsequent analyses, participants with diagnosed depressive disorders prior to retirement were excluded. The investigators found the highest incidence of depressive disorders among individuals who retired after 69 years of age (8.15 per 1000 person-years) and those who retired between 65 and 69 years of age (7.6 per 1000 person-years). This risk of developing a depressive disorder was higher among individuals retiring in the 65 to 69 age group compared with the 60 to 64 group (adjusted hazard ratio [aHR], 1.10; 95% CI, 1.02-1.18). Furthermore, the risk for depression was higher among women (aHR, 1.56; 95% CI, 1.47-1.65; P <.001), people living in rural areas (aHR, 1.11; 95% CI, 1.02-1.20; P =.015), and individuals with a Charlson Comorbidity Index of 1 (aHR, 1.40; 95% CI, 1.27-1.54; P <.001) or 2 and greater (aHR, 1.40; 95% CI, 1.28-1.52; P <.001). These study results indicate that retiring at a later age carries a higher risk of developing depression. The investigators concluded, “Instead of implying a beneficial mental effect of retirement, our results highlight that retirement represents a major life change and a potential stressor for older adults.” Study limitations include the use of insurance identities as proxy for retirement information, a lack of some demographic features, and an inability to identify individuals who may have depression but were not seeking medical help. References: Yang HJ, Cheng Y, Yu TS, Cheng WJ. Association between retirement age and incidence of depressive disorders: a 19-year population-based study. Am J Geriatr Psychiatry. Published online September 16, 2023. doi:10.1016/j.jagp.2023.09.010